Abstract ? Project 1 Obesity is a major health concern that is increasing in prevalence in the U.S. and worldwide, and disproportionately affects African Americans. It can lead to non-alcoholic fatty liver disease (NAFLD), which in turn can lead to liver cancer via chronic hepatitis, but the malignancy is asymptomatic until late stage when curative options are unavailable, leading to extremely high mortality. On the other hand, increasing knowledge of the mechanistic pathways by which NAFLD leads to cancer offers the possibility to develop early serum markers that can stratify patients into those at higher and lower risk: in turn, higher risk patients can undergo liver cancer surveillance to identify it early enough for curative surgery. The present proposal is a collaborative approach for research at Howard University (HU) and the Lombardi Comprehensive Cancer Center (LCCC) at Georgetown University to discover the molecular and genetic signatures of perturbed metabolic and mechanistic pathways in NAFLD patients in an African?American (AA) population receiving medical care for this condition at Howard University Hospital. Our overall objective is to identify candidate genes and genetic pathways associated with NAFLD, to find and fill the knowledge gaps of this extreme health disparity issue among AA around the Washington DC region. The two PIs of this pilot study ? Dr. Christopher Loffredo, a cancer epidemiologist at LCCC, and Dr. Charles Howell, a gastroenterologist and Chair of Internal Medicine at Howard University ? will co-mentor Dr. Ghosh, an early stage investigator at HU. Dr. Ghosh?s expertise is molecular genetics of chronic diseases. Leveraging these complementary areas of expertise, we propose to use pilot funding from this P20 proposal to enroll 50 NAFLD patients (cases) and 50 matched controls at Howard University: they will participate in an interview to provide information on personal and medical history, and will agree to a blood draw that will allow us to assess differences in levels of gene expression in cancer-relevant mechanistic pathways (e.g. inflammation) that are potential signatures of disease progression towards liver cancer. We will actively involve graduate and post-doctoral students in the laboratory work. In Specific Aim 1 we will apply a gene expression analysis (microarray coupled with IPA analysis) to divulge the differential gene expressions and their pathways in the two groups of subjects. In Specific Aim 2 we will validate the candidate disease markers by applying high-throughput TaqMan Low Density Arrays (TLDA). We will validate the precise panel of genes within the particular biological pathways and we will integrate clinical, epidemiologic and laboratory data to identify the robustness of these markers towards stability, validity, reproducibility, feasibility and utility of this new TLDA approach. The overreaching goal of this research is, therefore, to shed new light on possible mechanisms by which NAFLD may contribute to the dysregulation of important pre-cancer pathways. In turn, such knowledge will foster the identification of potential avenues for treatment and prevention for this minority population.